Carboxymethyl-γ-cyclodextrin, a novel selective relaxant binding agent for the reversal of neuromuscular block induced by aminosteroid neuromuscular blockers: an ex vivo laboratory study.

BACKGROUND: Residual neuromuscular block at the end of surgery may compromise the patient's safety. The risk of airway complications can be minimized through monitoring of neuromuscular function and reversal of neuromuscular block if needed. Effective reversal can be achieved with selective relaxant binding agents, however, sugammadex is the only clinically approved drug in this group. We investigated the concentration-response properties of a novel selective relaxant binding agent, carboxymethyl-γ-cyclodextrin for the reversal of neuromuscular block. We evaluated the hypothesis that it is equally potent for reversing neuromuscular block as sugammadex. METHODS: Phrenic nerve - hemidiaphragm tissue preparations were isolated from male Wistar rats and suspended in a tissue holder allowing electrical stimulation of the nerve and monitoring of muscle contraction force. Concentration-response relationships were constructed for the neuromuscular blocking agents rocuronium, pipecuronium, and vecuronium. The half-effective concentrations of sugammadex and carboxymethyl-γ-cyclodextrin for reversal of neuromuscular block were determined. RESULTS: The half effective concentrations (95% confidence interval, CI) were 7.50 (6.93-8.12) µM for rocuronium, 1.38 (1.33-1.42) µM for pipecuronium, and 3.69 (3.59-3.80) µM for vecuronium. The half effective concentrations (95% CI) of carboxymethyl-γ-cyclodextrin and sugammadex were 35.89 (32.67-39.41) µM and 3.67 (3.43-3.92) µM, respectively, for the reversal of rocuronium-induced block; 10.14 (9.61-10.70) µM and 0.67 (0.62-0.74) µM, respectively, for the reversal of pipecuronium-induced block; and 376.1 (341.9-413.8) µM and 1.45 (1.35-1.56) µM, respectively, for the reversal of vecuronium-induced block. CONCLUSIONS: Carboxymethyl-γ-cyclodextrin is an effective, but less potent agent for reversal of neuromuscular block than sugammadex.

Unanticipated Consequences of Switching to Sugammadex: Anesthesia Provider Survey on the Hormone Contraceptive Drug Interaction.

BACKGROUND: Sugammadex binds progesterone with high affinity and may interfere with hormonal contraceptive effectiveness. The clinical, economical, and ethical implications of unintended pregnancy should prompt anesthesiologists to actively consider and manage this pharmacologic interaction. We surveyed anesthesiology providers at our institution about knowledge of this potential adverse drug interaction, how they manage it clinically, and the extent to which they involve patients in shared decision-making regarding choice of neuromuscular blocker antagonist. METHODS: A survey instrument was distributed to anesthesiology providers at a large, tertiary-care medical center. The survey explored prior experience using neostigmine and sugammadex, knowledge about potential sugammadex interference with hormonal contraception, pre-/postoperative counseling practices, clinical management, and shared decision-making regarding potential use of neostigmine in lieu of sugammadex to avoid this drug-drug interaction. RESULTS: Of 259 surveys distributed, 155 were fully completed, and 10 were partially completed. Overall response rate was 60% (residents 85%, student nurse anesthetists 53%, certified registered nurse anesthetists 58%, attendings 48%). All but 1 respondent recognized the potential for sugammadex interference with oral hormonal contraception. Far fewer accurately identified potential interference with hormonal intrauterine devices (44%) and hormonal contraceptive implants (55%). The manufacturer's recommended 7-day duration of alternative contraception was correctly identified by 72% of respondents; others (22%) reported longer durations (range 10-30 days). Most (78% overall) agreed/strongly agreed that potential interference with contraceptive effectiveness should be discussed with patients preoperatively. Despite the majority (86% overall) that endorsed shared decision-making and inviting patient input regarding choice between sugammadex and neostigmine, many respondents reported "rarely/never" having discussed this drug interaction with patients in actual clinical practice, either preoperatively (67%) or postoperatively (80%). Furthermore, most respondents (79%) reported "rarely/never" administering neostigmine to intentionally avoid this drug interaction. CONCLUSIONS: Two years after designating sugammadex as antagonist of choice, physician and nurse anesthesia providers reported seldom inquiring about contraceptive use among women of childbearing potential and rarely discussing potential risk of contraceptive failure from sugammadex exposure. Most lack accurate knowledge of sugammadex interference with hormonal intrauterine and subcutaneous contraceptive devices. Although most endorse preoperative counseling and support patient autonomy or shared decision-making regarding choice of reversal agent, the same respondents report rarely, if ever, actualizing these positions in clinical practice. These conflicting findings highlight the need for education regarding residual neuromuscular block versus adverse drug interactions, collaboration among providers involved in patient counseling, and intentional mindfulness of reproductive justice when caring for women of childbearing potential.

In-Vitro Neutralization of the Neurotoxicity of Coastal Taipan Venom by Australian Polyvalent Antivenom: The Window of Opportunity.

Coastal taipan (Oxyuranus scutellatus) envenoming causes life-threatening neuromuscular paralysis in humans. We studied the time period during which antivenom remains effective in preventing and arresting in vitro neuromuscular block caused by taipan venom and taipoxin. Venom showed predominant pre-synaptic neurotoxicity at 3 µg/mL and post-synaptic neurotoxicity at 10 µg/mL. Pre-synaptic neurotoxicity was prevented by addition of Australian polyvalent antivenom before the venom and taipoxin and, reversed when antivenom was added 5 min after venom and taipoxin. Antivenom only partially reversed the neurotoxicity when added 15 min after venom and had no significant effect when added 30 min after venom. In contrast, post-synaptic activity was fully reversed when antivenom was added 30 min after venom. The effect of antivenom on pre-synaptic neuromuscular block was reproduced by washing the bath at similar time intervals for 3 µg/mL, but not for 10 µg/mL. We found an approximate 10-15 min time window in which antivenom can prevent pre-synaptic neuromuscular block. This time window is likely to be longer in envenomed patients due to the delay in venom absorption. Similar effectiveness of antivenom and washing with 3 µg/mL venom suggests that antivenom most likely acts by neutralizing pre-synaptic toxins before they interfere with neurotransmission inside the motor nerve terminals.

Sugammadex by ideal body weight versus 20% and 40% corrected weight in bariatric surgery - double-blind randomized clinical trial / Uso de sugamadex pelo peso corporal ideal versus corrigido em 20% e 40% em cirurgia bariátrica - ensaio clínico randômico e duplo-cego

Abstract Background and objectives: The weight parameters for use of sugammadex in morbidly obese patients still need to be defined. Methods: A prospective clinical trial was conducted with sixty participants with body mass index ≥ 40 kg.m-2 during bariatric surgery, randomized into three groups: ideal weight (IW), 20% corrected body weight (CW20) and 40% corrected body weight (CW40). All patients received total intravenous anesthesia. Rocuronium was administered at dose of 0.6 mg.kg-1 of Ideal weight for tracheal intubation, followed by infusion of 0.3-0.6 mg.kg-1.h-1. Train of four (TOF) was used to monitor depth of blockade. After spontaneous recovery TOF-count 2 at the end of surgery, 2 mg.kg-1 of sugammadex was administered. Primary outcome was neuromuscular blockade reversal time to TOF ≥ 0.9. Secondary outcome was the occurrence of postoperative residual curarization in post-anesthesia recovery room, searching the patient's ability to pass from the surgical bed to the transport, adequacy of oxygenation, respiratory pattern, ability to swallow saliva and clarity of vision. Results: Groups were homogenous in gender, age, total body weight, ideal body weight, body mass index, type and time of surgery. The reversal times (s) were (mean ± standard deviation) 225.2 ± 81.2, 173.9 ± 86.8 and 174.1 ± 74.9 respectively, in the IW, CW20 and CW40 groups (p = 0.087). Conclusions: No differences were observed between groups with neuromuscular blockade reversal time and frequency of postoperative residual curarization. We concluded that ideal body weight can be used to calculate sugammadex dose to reverse moderate neuromuscular blockade in morbidly obese patients.

Resumo Justificativa e objetivos: Os parâmetros de peso para o uso de sugamadex em pacientes com obesidade mórbida ainda precisam ser definidos. Métodos: Um ensaio clínico prospectivo foi feito com 60 participantes com índice de massa corporal ≥ 40 kg.m-2, submetidos a cirurgia bariátrica, randomizados em três grupos: peso ideal (PI), peso corrigido em 20% (PC20) e peso corrigido em 40% (PC40). Todos os pacientes receberam anestesia intravenosa total. Rocurônio foi administrado em dose de 0,6 mg.kg-1 para intubação traqueal pelo peso ideal, seguido de infusão (0,3 a 0,6 mg.kg-1.h-1). A sequência de quatro estímulos (TOF) foi usada para monitorar a profundidade do bloqueio. Após recuperação espontânea da segunda resposta do TOF no fim da cirurgia, 2 mg.kg-1 de sugamadex foi administrado. O desfecho primário foi o tempo de reversão do bloqueio neuromuscular até obter TOF ≥ 0,9. O desfecho secundário foi a ocorrência de curarização residual pós-operatória na sala de recuperação pós-anestésica, avaliaram-se a capacidade do paciente de passar do leito cirúrgico para o de transporte, a adequação da oxigenação, o padrão respiratório, a habilidade para deglutir saliva e a clareza de visão. Resultados: Os grupos foram homogêneos quanto a gênero, idade, peso corporal total, peso corporal ideal, índice de massa corporal, tipo e tempo de cirurgia. Os tempos de reversão (segundos) foram (média ± desvio-padrão) 225,2 ± 81,2, 173,9 ± 86,8 e 174,1 ± 74,9, respectivamente, nos grupos PI, PC20 e PC40 (p = 0,087). Conclusões: Não foram observadas diferenças entre os grupos quanto ao tempo de reversão do bloqueio neuromuscular e frequência de curarização residual pós-operatória. Concluímos que o peso corporal ideal pode ser usado para calcular a dose de sugamadex para reverter o bloqueio neuromuscular moderado em pacientes com obesidade mórbida.

Rattling the border wall: Pathophysiological implications of functional and proteomic venom variation between Mexican and US subspecies of the desert rattlesnake Crotalus scutulatus.

While some US populations of the Mohave rattlesnake (Crotalus scutulatus scutulatus) are infamous for being potently neurotoxic, the Mexican subspecies C. s. salvini (Huamantlan rattlesnake) has been largely unstudied beyond crude lethality testing upon mice. In this study we show that at least some populations of this snake are as potently neurotoxic as its northern cousin. Testing of the Mexican antivenom Antivipmyn showed a complete lack of neutralisation for the neurotoxic effects of C. s. salvini venom, while the neurotoxic effects of the US subspecies C. s. scutulatus were time-delayed but ultimately not eliminated. These results document unrecognised potent neurological effects of a Mexican snake and highlight the medical importance of this subspecies, a finding augmented by the ineffectiveness of the Antivipmyn antivenom. These results also influence our understanding of the venom evolution of Crotalus scutulatus, suggesting that neurotoxicity is the ancestral feature of this species, with the US populations which lack neurotoxicity being derived states.

Effects of neostigmine or edrophonium on force of contraction when administered at a train-of-four ratio of 0.9 in anesthetized dogs.

OBJECTIVE: Anticholinesterase drugs may produce paradoxical neuromuscular block when administered at shallow levels of neuromuscular block. The objective of this study was to evaluate the effects of neostigmine and edrophonium when administered at near-complete reversal from nondepolarizing block in anesthetized dogs. STUDY DESIGN: Incomplete crossover, randomized, blinded experimental study. ANIMALS: A total of 12 Beagle dogs. METHODS: Each dog was anesthetized twice with propofol and maintained with isoflurane and dexmedetomidine. Intravenous (IV) vecuronium (0.1 mg kg-1) was administered. When the mechanographic train-of-four (TOF) ratio had spontaneously recovered to ≥0.9, either neostigmine (0.04 mg kg-1) or edrophonium (0.5 mg kg-1) was administered IV, preceeded by atropine. Changes in twitch height or TOF ratio were measured for the next 10 minutes. Recurarization was considered to be present if values decreased by ≥10%. RESULTS: Data from four dogs in each treatment were excluded from analysis, resulting in data from five dogs administered both treatments, three dogs administered neostigmine and three dogs administered edrophonium. There was no difference between groups for age, weight, T1 and T4 twitch heights or TOF ratio values, before or after anticholinesterase administration. The TOF ratio decreased by 17% and 18% in two of the eight dogs administered neostigmine, resulting from a larger increase in T1 relative to T4. No reductions in individual twitch amplitudes were recorded in those dogs. When edrophonium was used, no cases of recurarization were observed. CONCLUSIONS AND CLINICAL RELEVANCE: The results support use of edrophonium for reversal of shallow neuromuscular block. The decreases in TOF ratio recorded after neostigmine does not necessarily indicate muscular weakness. Although the clinical implications are uncertain, the results suggest that, at these doses, edrophonium may be preferable to neostigmine for reversal of shallow neuromuscular block in dogs.

Incidence of complications in the post-anesthesia care unit and associated healthcare utilization in patients undergoing non-cardiac surgery requiring neuromuscular blockade 2005-2013: A single center study.

STUDY OBJECTIVE: The use of neuromuscular blockade agents (NMBA), had been associated with significant residual post-operative paralysis and morbidity. There is a lack of clinical evidence on incidence of postoperative complications within the post-anesthesia care unit (PACU) in patients exposed to intraoperative NMBA's. This study aims to estimate the incidence of post-operative complications associated with use of NMBAs and assessing its association with healthcare resource utilization. DESIGN: Retrospective cohort. SETTING: Post-anesthesia care unit in tertiary care center. PATIENTS: Adults having non-cardiac surgery and receiving NMBAs between April-2005 and December-2013 MEASUREMENTS: We assessed: 1) incidences of major and minor PACU complications, 2) incidence of any postoperative complication in patients receiving a NMBA reversal (neostigmine) vs. without. 3) We secondarily assessed the relationship between PACU complications and use of healthcare resources. MAIN RESULTS: The incidence of any major complications was 2.1% and that of any minor complication was 35.2%. ICU admission rate was 1.3% in patients without any complications, versus 5.2% in patients with any minor and 30.6% in patients with any major complication. ICU length of stay was prolonged in patients with any major (52.1±203h), compared to patients with any minor (6.2±64h) and with no complications (1.7±28h). Patients who received a NMBA and neostigmine, compared to without neostigmine, had a lower incidence of any major complication (1.7% vs. 6.05%), rate of re-intubation (0.8% vs. 4.6%) and unplanned ICU admission (0.8% vs. 3.2%). CONCLUSIONS: This study documents that incidence of major PACU complications after non-cardiac surgery was 2.1%, with the most frequent complications being re-intubation and ICU admission. Patients receiving NMBA reversal were at a lower risk of re-intubation and unplanned ICU admission, justifying routine use of reversals. Complete NMBA reversals are crucial in reducing preventable patient harm and healthcare utilization.

Does Sugammadex Administration Affect Postoperative Nausea and Vomiting After Laparoscopic Cholecystectomy: A Prospective, Double-Blind, Randomized Study.

BACKGROUND: The aim of this study is to assess the effect of sugammadex on postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic cholecystectomy. METHODS: Eighty patients who were scheduled for elective laparoscopic cholecystectomy surgery were enrolled in this prospective study. Patients were randomly assigned to neostigmine (group N) or sugammadex (group S) for neuromuscular antagonism at the end of anesthesia. The incidence of PONV and antiemetic consumption were recorded. RESULTS: Nausea and vomiting were observed in 60% of the patients given sugammadex and 77.5% given neostigmine during the initial 24 hours postoperatively. The incidence of nausea and the need for rescue antiemetic were lower in group S than group N during all time intervals but there were no significant differences between the groups. CONCLUSIONS: Sugammadex seems to be effective in decreasing the incidence of PONV, severity of nausea, number of patients who suffered from nausea and vomiting, and need for rescue antiemetic, although there were no significant differences.

[Residual neuromuscular blockade]. / Neuromuskuläre Restblockade.

Even small degrees of residual neuromuscular blockade, i. e. a train-of-four (TOF) ratio >0.6, may lead to clinically relevant consequences for the patient. Especially upper airway integrity and the ability to swallow may still be markedly impaired. Moreover, increasing evidence suggests that residual neuromuscular blockade may affect postoperative outcome of patients. The incidence of these small degrees of residual blockade is relatively high and may persist for more than 90 min after a single intubating dose of an intermediately acting neuromuscular blocking agent, such as rocuronium and atracurium. Both neuromuscular monitoring and pharmacological reversal are key elements for the prevention of postoperative residual blockade.

Glycopyrrolate: It's time to review.

Medication shortages have become an all-too-common inconvenience that has forced anesthesia providers to examine our administering practices. Because of these shortages, commonly used medications are at the greatest risk. Glycopyrrolate (Robinul), which has been in short supply in recent years, is one of the most widely used anticholinergic agents, especially in conjunction with the anticholinesterase neostigmine, for reversal of neuromuscular blockade (NMB) drugs. Here we review multiple studies from 1972 through 1986 that used varying methods of patient selection and dosage and drug combination criteria, and which noted that glycopyrrolate had a superior efficacy and adverse effect profile when compared with atropine in NMB reversal. Meta-analysis from these studies indicated that the dosage of 0.2 mg of glycopyrrolate for every 1 mg of neostigmine, given concomitantly (maximum 1 mg glycopyrrolate and 5 mg neostigmine), demonstrated the greatest efficacy with the lowest incidence of unwanted adverse effects. It has now become common practice to use a dosage ratio of 0.2 mg glycopyrrolate to 1.0 mg neostigmine for NMB reversal. Yet since 1986, there have been no studies on reversal with glycopyrrolate and neostigmine. Frequent medication shortages and good medical practice should be an impetus for clinicians to reevaluate dosing practices of critical medications and revisit these drugs, such as glycopyrrolate, with more current studies.

Optimum dose of neostigmine to reverse shallow neuromuscular blockade with rocuronium and cisatracurium.

We examined the use of neostigmine for reversing shallow (defined as train-of-four ratio of 0.5), cisatracurium- and rocuronium-induced neuromuscular block in 112 patients, by use of 0 µg.kg(-1) , 10 µg.kg(-1) , 20 µg.kg(-1) or 40 µg.kg(-1) dose of neostigmine for reversal. The times from neostigmine administration to train-of-four ratios of 0.7, 0.9 and 1.0 were evaluated. Analysis of variance showed that the duration of action was significantly longer after cisatracurium compared with rocuronium. The time to reach a train-of-four ratio of 1.0 was significantly shorter with neostigmine 40 µg.kg(-1) compared with lower neostigmine doses, and at this dose the time did not differ between cisatracurium and rocuronium. The recovery time from a train-of-four ratio of 0.5-1.0 did not differ between cisatracurium and rocuronium, and was significantly shortened by the administration of neostigmine. We conclude that a neostigmine dose of 40 µg.kg(-1) was the most effective at reducing recovery time after neuromuscular blockade.

[When muscle relaxants have unexpected prolonged duration during anaesthesia]. / Uventet lang virkningsvarighed afmuskelrelaksantia kan forebygges

Muscle relaxation facilitates tracheal intubation and improves surgical conditions during anaesthesia. However, unexpected prolonged muscle relaxation may occur. This article describes important causes of prolonged muscle relaxation and gives suggestions for its prevention. Drug interactions, incomplete reversal, co-morbidity, inaccurate neuromuscular monitoring and critical illness may prolong the effect of muscle relaxants. The anaesthetist must titrate the muscle relaxants using objective neuromuscular monitoring and proper reversal of the blockade when needed.

Neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of autosomal-recessive centronuclear myopathy.

BACKGROUND: Centronuclear myopathy (CNM) is a rare congenital condition associated with skeletal muscle weakness. Patients with CNM may have decreased acetylcholine receptor expression and a reduced number of releasable quanta. Such perturbations could affect the time-course of neuromuscular blocking agents (NMBAs) and their antagonism with cholinesterase inhibitors. As a result of the rarity of CNM, prospective data regarding NMBA use in this subpopulation is scarce. We evaluated the neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of CNM. METHODS: Six dogs with congenital autosomal-recessive CNM and six controls received cisatracurium 0.15 mg kg(-1) i.v. under general anaesthesia and intermittent positive pressure ventilation. Neuromuscular function was monitored with acceleromyography.When the second response (T2) to train-of-four (TOF) stimulation returned, neostigmine 0.04 mg kg(-1) (with glycopyrrolate) were administered i.v. The onset time, time to spontaneous return of T2, and the time to reach a TOF ratio ≥0.9 after neostigmine administration were recorded. RESULTS: Onset time was no different between groups. Median (interquartile range) time to return of T2 was 27 (24-31) min for control dogs and 26 (22-31) min for CNM dogs (P=0.93).After neostigmine administration, a TOF ratio ≥0.9 was reached in 12 (10-15) min and 17 (16-19) min in control and CNM, respectively (P=0.005). CONCLUSIONS: The spontaneous return of T2 was not different between groups. However, neostigmine-facilitated recovery was significantly slower in dogs with CNM. Canine autosomal-recessive CNM does not preclude the use of cisatracurium or its antagonism with neostigmine.

Management of neuromuscular blockade in ambulatory patients.

PURPOSE OF REVIEW: The use of neuromuscular blocking agents in ambulatory surgery has been described as a double-edged sword. Muscle relaxants may improve the outcome following endotracheal intubation and could be helpful for the surgeon to some extent. However, these agents might increase the risk of postoperative complications because of residual paralysis. This review should summarize recent developments in neuromuscular blockade, neuromuscular monitoring, and reversal with a special reference to day case surgery. RECENT FINDINGS: The use of neuromuscular blocking agents begs a risk of postoperative muscle weakness and has been associated with adverse respiratory events. From the surgical side, there could be an increased request for a more intense neuromuscular block during laparoscopic surgery. Therefore, the use of quantitative neuromuscular monitoring and selective reversal binding agents may gain more importance in the future. For the reversal of a shallow neuromuscular block, cholinesterase inhibitors are still appropriate. SUMMARY: The management of neuromuscular blocks in day case surgery requests a comprehensive approach that should include an adequate dosing of the muscle relaxant, quantitative objective monitoring, and a sufficient and appropriate reversal.

Rapid reversal of neuromuscular blockade by sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery.

OBJECTIVE: Sugammadex rapidly reverses neuromuscular blockade (NMB) induced by rocuronium. NMB induced by rocuronium is prolonged in patients with liver dysfunction, because the drug is mainly excreted into the bile. However, the efficacy and safety of sugammadex in terms of reversing rocuronium-induced NMB in patients with liver dysfunction undergoing hepatic surgery have not been evaluated. This observational study investigated the efficacy and safety of sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. METHODS: Remifentanil/propofol anesthesia was administered to 31 patients: 15 patients in the control group, and 16 patients from a group with liver dysfunction. Rocuronium (0.6 mg/kg) was administered, followed by continuous infusion. The enrolled patients were then subdivided into two groups according to the dose of sugammadex. In the first group a single dose of sugammadex (2.0 mg/kg) was given at the reappearance of the second twitch (T2). In the second group a single dose of sugammadex (4.0 mg/kg) was given at the first twitch response if T2 did not reappear in 15 minutes after stopping rocuronium. The primary outcome was time from administration of sugammadex to recovery of a train-of-four ratio to 0.9. RESULTS: The dose of rocuronium required in the liver dysfunction group was lower than that in the control group (6.2 vs. 8.2 µg/kg/min, p = 0.002). The mean time from the administration of sugammadex to recovery of the train-of-four ratio to 0.9 was not significantly different between the liver dysfunction group and the control group (2.2 minutes vs. 2.0 minutes in the 2 mg/kg administration group, p = 0.44 and 1.9 minutes vs. 1.7 minutes in the 4 mg/kg administration group, p = 0.70, respectively). No evidence of recurarization was observed in any of the patients. Most of the adverse events were found to be mild and such events were not related to the use of sugammadex. None of the patients was eliminated from the study because of an adverse event. One patient died due to cholestatic liver cirrhosis because of repeated hepatic surgery. CONCLUSION: Sugammadex can rapidly reverse NMB after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Sugammadex was found to be safe and well tolerated. However, further studies of sugammadex under similar conditions should be conducted involving a large number of patients with liver dysfunction undergoing hepatic surgery.